11-oxygenated-6-methyl-9alpha-fluoro-pregnadienes and esters thereof



United States Patent 11-OXYGENATED-6-METHYL-9a-FLUGRO-PREG- NADIENES ANDESTERS THEREOF George B. Spero, Kalamazoo, Mich., assignor to The UpjohnCompany, Kalamazoo, Mich., a corporation of Delaware No Drawing. FiledJuly 27, 1959, Ser. No. 829,517

6 Claims. (Cl. 260-39145) wherein X is a halogen of atomic numberbetween seventeen and 35, inclusive, and R is selected from the groupconsisting of hydrogen and acyl, wherein the acyl radical is selectedfrom the group consisting of organic carboxylic acids, preferablyhydrocarbon carboxylic acids containing from one to twelve carbon atoms,inclusive, and methanesulfonic acid.

The process of the present invention comprises: dehydrating al-dehydro-6-methylhydrocortisone 2l-ester or the free alcohol (I)illustratively with sulfuric acid or preferably with a hypohalous acidand then with anhydrous sulfur dioxide to obtain the corresponding6-methyl- 17a,2l dihydroxy 1,4,9(11) pregnatriene 3,20 dione 21-ester orrespectively the free alcohol (II). Addition of a hypohalous acid suchas hypochlorous or hypobromous acid results in6-methyl-9a-halo-ll/3,17u,21-trihydroxy-l,4-pregnadiene-3,20-dioneacylate or the free alcohol (III), which by treatment with a base suchas anhydrous potassium acetate yields the epoxy compound 6-rnethyl-9,B,l 15-oxido-17a,21-dihydroxy-1,4-pregnadiene-3, 20-dione21-acylate or, respectively, the unesterified product, both representedby Formula IV. Treatment of the epoxy compound (IV) with hydrogenfluoride or other hydrogen fluoride releasing agents provides thephysiologically-active fiuoro derivative, 6-methyl-9a-fiuoro-l15,1711,2l-trihydroxy-l,4-pregnadiene-3,20 dione 2l-acylate or the free trioll-dehydro-6-methyl-9a-fluorohydrocortisone, represented by Formula V.Oxidation of the esterified compound (V) with chromic acid in aceticacid provides the 6-methyl-9a-fiuoro-l7a,2l-dihydroxy-1,4-pregnadiene-3,11,20-trione 21-acylate (VI). Hydrolysis of the ester VI with a baseprovides the free alcohol 6-methyl-l7a,21- dihydroxy 1,4 pregnadiene3,11,20 trione (1 dehydro 6 methyl 9a fiuorocortisone).

it is an object of the instant invention to provide the newadrenocortical hormones, 1 dehydro 6 methyl- 9:): fiuorohydrocortisone,l dehydro 6 methyl 9afiuorocortisone and the 2l-esters thereof, inparticular in the oa-epi-meric form. It is another object of the instantinvention to provide a method for the production of 1- dehydro 6 methyl9a fiuorohydrocortisone, 1 dehydro 6 methyl 9a fiuorocortisone and the21 esters thereof. It is an additional object of the instant inventionto provide the intermediates for the production of theseadrenocortically active compounds, such as 6- methyl 170:,21 dihydroxy1,4,9(ll) pregnatriene- 3,20 dione 21 acylate, 6 methyl 9(11) oxido 17a,21 dihydroxy 1,4 pregnadiene 3,20 dione 21- acylate, the chloroand 9abromo 6 methyl- 11[3,17x,2l trihydroxy 1,4 pregnadiene 3,20 dione2l-acylates and the free alcohols thereof. Other objects of thisinvention will be apparent to those skilled in the art to which thisinvention pertains.

The novel 1 dehydro 6 methyl 9a fluorohydrocortisone, the 1 dehydro 6methyl 9a fiuorocortisone and the 21-esters thereof, in particular the6mepimers thereof, i.e., 1 dehydro 6a methyl 9afluorohydrocortisone and1 dehydro 6a methyl 9afiuorocortisone, are very active adrenal corticalhormones possessing anti-inflammatory activity of an extremely highorder and possessing improved therapeutic ratio. They are thus useful inparenteral and topical compositions and may be given as tablets for oraluse in combination with such binding materials and carriers aspolyethylene glycol 4000 or 6000, lactose, sucrose, and the like;Especially useful is the 1 dehydro 6a methyl 9a fluorohydrocortisone andesters thereof for this purpose. In topical application the substancesan be used as ointments, lotions, jellies, creams, suppositories,bougies, aqueous suspensions, and the like. Instead of the 1 dehydro-*6oz methyl 9a fluorohydrocortisone or 1 dehydro- 6a methyl 9ozfiuorocortisone, the 6B epimers thereof can be used in therapeuticallyequivalent amounts to give the same final results. 7 p

pohalite with dry sulfur dioxide in an organic base.

The starting materials of the instant invention are the1-dehydro-6a-methylhydrocortisone esters as described in Preparations 1through 14. Instead of the l-dehydro-amethylhydrocortisone, the6/8-epimer can be used to give the corresponding1-dehydro-6{3-methyl-9a-fiuorohydrocortisone and the1-dehydro-6,8-methyl-9a-fiuorocortisone.

In carrying out the process of the instant invention, 6- methyl-l1,8,17a,21-tri11ydroxy-1,4,pregnadiene-3,ZO-dione ZI-acylate(1-dehydro-6-methylhydrocortisone 21-acylate) is dehydrated to thecorresponding 2l-acylate of 6- methyl 1701,21dihydroxy-1,4,9(l.l)-pregnatriene-3,20- dione by methods known in theart, for example, by a dehydrating agent such as phosphorus oxychloride,hydrochloric acid or sulfuric acid and acetic acid, or pyrolysis asshown by US. Patents 2,640,838 and 2,640,839. In the preferredembodiment of the present invention the dehydration is effected byreacting the llfi-hydroxy compound with an N-haloamide or N-haloimide inan organic base and treating the thus produced intermediate 11-hy- Asreagents for the production of an ll-hypohalite, the N- haloamide orN-haloimide are used wherein the halogen has an atomic number from 17 to5 3, inclusive, preferably chlorine or bromine. Examples of suchcompounds are N-chloroacetamide, N-bromoacetamide, N-chlorosuccinimide,N-brornosuccinimide, N-iodosuccinimide, 3- bromo-5,5-dimethylhydantoinand 1,3-dibromo-5,5-dimethylhydantoin. Ordinarily an amount in excess ofa molar equivalent, calculated on the starting llfi-hydroxy steroid, isemployed. The bases employed in the production of the ll-hypohalite aretertiary amines wherein the amino nitrogen is a member of an aromaticring, for example, the pyridines, that is, pyridine, alkyl-pyridines,

piccoline, lutidine, collidine, conyrine, parvuline, or the like, orlower fatty amides such as formamide, methylformamide anddimethylformamide. The base is preferably employed in a large molarexcess, calculated on the starting 11,8-hydroxy steroid, for example,ten molar equivalents, and is preferably the sole reaction solvent. Thereaction to produce an ll-hypohalite is generally conducted underanhydrous conditions preferably containing less than 0.1 molarequivalent of water calculated per mole of steroid. Large proportions ofwater decrease the yield. The temperature of the reaction is betweenminus forty and plus seventy degrees centigrade, the lower limit beingdetermined by the solubility of the reagents in the solvents and theupper limit being determined by the amount of side reaction whichnormally accompanies the reaction involving any halo compounds at highertemperatures. Ordinarily, room temperature (twenty to thirty degreescentigrade) is preferred for convenience and the consistently highyields of the desired product which are obtained at this temperature. Areaction period between five minutes to three hours is usually employed,at higher temperatures-above thirty degrees centig'rade-short reactiontimes are sufficient to produce completeness of the reaction.

The thus produced 6-methyl-11B,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione lle-hypohalite, 21-acylate is then treated withanhydrous sulfur dioxide in the presence of an organic base as describedhereinbefore. The anhydrous sulfur dioxide can be in the form of gaseousor liquid sulfur dioxide or in the form of a material which in situproduces sulfur dioxide, for example, alkali metal hyposulfite. Thereaction temperature ranges substan tially within minus forty and plusseventy degrees centigrade and preferably room temperature (twenty tothirty degrees centigrade). The thus obtained product, a 6-methyl-17oz,21-dihydroxy-i,4,9(11) pregnatriene 3,20- dione 21-acylate,is isolated from the reaction mixture by' conventional means such asextraction after the reac tion mixture has been poured into excess ofwater. Org'anic water-immiscible solvents such as ether, chloroform,methylene chloride, carbon tetrachloride, ethyl acetate, benzene,hexanes, or the like, are used for the extraction. The thus obtainedextracts are conveniently washed, dried and thereupon evaporated to givethe crude 6 methyl-17:121-dihydroxy-1,4,9(11)-pregnatriene-3,2O- dione21-ester which is purified by conventional means such asrecrystallization 0r chromatography, as deemed necessary.

The thus obtained 6-methyl-17a,2l-dihydroxy-IA,9(11)-pregnatriene-3,20-dione 21-acylate is converted to 6 methyl 9ahalo 1lfi,l7a,2l-trihydroxy-I,4-pregnadiene-3,20-dione 21-acylate byadding a hypohalous acid such as hypoch-lorous or hypobromous acid. Thehypohalous acid is usually added by reacting an N-halo acid amide or anN-halo acid imide with an acid to produce the hypohalous acid in situ.In the preferred embodiment of the invention, the steriod, a6-m'ethyl-17u,21-dihydroxy-1,4,9(11)-pregnatriene-3,20-dione 2l-ester isdissolved in an organic solvent such as methylene chloride, tertiarybutylalcohol, dioxane, tertiary amyl alcohol, or the like, and reactedat room temperature with the hypobromous or hypochlorous acid releasingagent in the presence of an acid. Such hypohalous acid releasing agentsinclude the N-bromoacetamide, the N-chloroacetamide, theN-bromosuccinimide, the N-iodosuccinimide, or the like, in the presenceof water and an acid such as per chloric acid, dilute sulfuric acid, orthe like. The reaction is usually carried out at room temperature,between fifteen to thirty degrees centigrade, however, lower or highertemperatures are operative for the process. The hypohalous acidreleasing agent is generally used in one molar or slightly increased,for example, 25 percent increased amounts compared to mole of steriod. Alarge excess of the hypohalous acid releasing agent while operative is'undesirable since the excess of hypohalous acid has a tendency to reacton other positions of the molecule. The reaction period is rather shortand may vary between about four to five minutes to one hour. At the endof the reaction time excess of hypohalous acid is destroyed by theaddition of sodium sulfite or other sulfites or hydrosulfites. The thusproduced product. a 6- methylhalo-115,17a,2l-trihydroxy-1,4-pregnadiene- 3,20-dione 21-acylate,wherein the halogen atom is of atomic weight between 33 and (atomicnumber 17 to 53), is isolated from the reaction mixture by adding excessof water and extracting the compound with organic solvents or byrecovering the precipitated compound through filtration. The crudeproduct thus obtained may be recrystallized from organic solvents, suchas acetone, Skellysolve B hexane hydrocarbons or the like to give pure6-methyl-9a-halo-1 1/3,17a,2 l-trihydroxy-1,4-pregnadiene-3,20-dione21-acylate.

The ester thus obtained can be hydrolyzed to give the free triol, 6methyl 9a-halo-1119,17a,21-trihydroxy-l,4- pregnadiene-3,20-dione, whichcan be reesterified.

Oxidizing the ZI-ester of a 6-methyl-9a-halo-11B,17a,21- trihydroxy 1,4pregnadiene 3,20-dione 21-acylate with chromic acid produces thecorresponding pharmaceutically active 6 methyl 9a halo17a,21-dihydroxy-l,4- pregnadiene-3,l1,20-trione 21-acylate which byhydrolysis gives the free trial 6-methyl-9a-halo-l7a,2l-dihydroxy-1,4-pregnadiene-3 ,1 1,20-trione.

In order to obtain the 9tx-fiuoro compounds, the 93,116- epoxyintermediates of the before-mentioned compounds, 6 methyl 9B,11fi oxido17a,21 dihydroxy 1,4- pregnadiene-3,20-dione 21-esters, are prepared. Incarrying out this reaction a6-methyl-9a-halo-11,3,17a,21-trihydroxy-l,4pregnadiene-3,ZO-dioneZl-ester is heated in solution with a mild base, and preferably in theabsence of water to avoid hydrolysis of the ester groups.

The bases useful for the cyclization include anhydrous potassiumacetate, sodium bicarbonate, sodium acetate, or the like, with potassiumacetate preferred. Solvents such as methanol, ethanol, acetone, tertiarybutyl alcohol, or the like, may be used. The reaction time is betweenone half hour and 24 hours; generally a period between three and twelvehours is sufficient. The thus obtained 6 methyl 9 3,115 4 oxido 1704,21dihydroxy 1,4- pregnadiene-3,20-dione 2l-acylate is isolated from thereaction mixture by diluting the reaction mixture with excess water andfiltering the product when crystalline, or by extracting with methylenechloride or other waterimmiscible solvents such as ether, Skellysolve Bhexanes, pentanes, benzene, ethyl acetate, chloroform, carbontetrachloride, or the like. Evaporation of the solvent of the extractsproduces the 6-'nethyl-9[3,11,8-oxido17a,21-dihydroxy-1,4-pregnadiene-3,20-dione 21-acylate.

'Ihe thus obtained6-methyl-9e,1IB-oxido-lhJl-d-ihydroxy-l,4-pregnadiene-3,20-dione2l-acylate is thereupon reacted with 48 percent hydrofluoric acid insolution. As solvents for this reaction methylene chloride, ethylenedichloride, chloroform, carbon tetrachloride or the like is useful, withmethylene chloride preferred. The reaction is carried out at roomtemperature (twenty to thirty degrees centigrade) preferably withstirring. The period of reaction is from one to 24 hours with a periodfrom one to twelve hours usually sufficient. After the reaction isterminated, the mixture is poured into water and neutralized with adilute base such as sodium bicarbonate, potassium bicarbonate, or thelike. Excess of strong bases can also be used. The reaction mixture isthen extracted with a water-immiscible solvent such as methylenechloride, the organic layer is separated from the water mixture, washedwith water, dried and evaporated to give the crude6-methyl-9a-fluoro-ll,8,17a,21- trihydroxy 1,4 pregnadiene 3,20 dione 21acylate. The thus obtained crude compound may be purified throughrecrystallization or chromatography.

The 6-methyl-9ot-fiuoro-11,6,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione 2l-esters obtained bythis process can be hydrolyzed to give the6-methyl-9a-fiuoro-l1fi,l7a,21- trihydroxy-l,4-pregnadiene-3,20-dionewhich can be reesterified, if desired, with acyl halides or acidanhydrides, in pyridine solution at room temperature to give other2l-esters of 6-methyl-9m-fiuoro-115,17a,2l-trihydroxy-1,4-pregnadiene-3,20-dione (1-dehydro-6-methyl-9a-fiuorohydrocortisone)Oxidation of the6-methyl-9a-fluoro-l1B,17oc,21-trihydroxy-l,4-pregnadiene-3,20-dione21-acylate with chromic acid produces the corresponding6-methyl-9a-fluoro-l7m, 21 dihydroxy 1,4 pregnadiene 3,11,20 trione 21-acylate which can be hydrolyzed illustratively with a base e.g., withsodium carbonate in ethanol in a nitrogen atmosphere to give the freediol, 6-methyl-9a-fluoro-l7ot, 21 -dihydroxy-1 ,4-pregnadiene-3 ,11,20-trione.

Using 6-methylhydrocortisone Zl-acylate instead of the1-dehydro-6-methylhydrocortisone 21-acylate in the above sequence ofreactions provides the 6-methyl-9a-fluorohydrocortisone and6-methyl-9a-fluorocortisone and their 21-estcrs which compounds havestrong anti-inflammatory and glucocorticoid activity. Both6-methyl-9ot-fiuorohy drocortisone and 6-methyl-9a-fluorocortisone aretherefore useful for topical uses as ointments for inflammatoryconditions, or internally, as tablets, for arthritic syptoms. Similarly,by using other 6-alkylor 6-phenyl-l-dehydrohydrocortisones as startingmaterial, the corresponding 1-dehydro-6-alkyl-9ot-fluorohydrocortisones,1-dehydro-6- alkyl-9a-fluorocortisones, the esters thereof and the 6-aryl analogues thereof are obtained, wherein the alkyl group is, forexample, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, orthe like and the aryl group is, for example, phenyl.

The following preparations and examples are illustrated for the processand products of the present invention, but are not to be construed aslimiting.

PREPARATION l 50:,6a oxido 115,] 711,21 trilzydrxyall0pregnane-3,20-dione 3,20-bis-(ethylene ketal) To a solution of 0.901 gram of1l;3,l7cc,2l-trihydroxy- -preguene-3,20-dione 3,20-bis-(ethylene ketal)in eighteen milliliters of chloroform was added a solution of 331milligrams of perbenzoic acid in 5.19 milliliters of chloroform. Theresulting solution was allowed to stand in the refrigerator (ca. fourdegrees centigrade) for a period of 24 hours and thereupon at roomtemperature for an additional period of 72 hours. The reaction solutionwas then washed with five percent sodium bicarbonate solution and water,dried over anhydrous sodium sulfate and evaporated to dryness to give1.031 grams of crude solid. Recrystallization from acetone gave 431milligrams of material of melting point 230 to 247 degrees centigrade.The mother liquor, after evaporation to dryness, was dissolved inmethylene chloride and chromatographed over 25 grams of acid washedalumina. The column was developed with three fractions each of methylenechloride plus five, ten, fifteen, twenty, 25 and fifty percent acetone,acetone, and acetone plus five per} cent methanol. The acetone plus fivepercent methanol eluate gave an additional 279 millgrams of the highmelting product. The high melting material, 50:,6oz-OXiClO- 11B,17oc,21trihydroxy allopregnane 3,20 dione 3,20-bis-(ethylene ketal) was threetimes recrystallized from acetone and methanol to give a pure product ofmelting point 263 to 268 degrees centigrade. ()ther eluate fractions oflower melting point contained the 5,8,6/3-iso-mer thereof.

In the same manner as shown in Preparation 1, other 50:,6a oxido1lfl,l7e,21 tr-ihydroxyallopregnane- 3,20-dione 3,20-bis-(allkyleneketals) can be prepared by reacting hydrocortisone diketals, wherein theketal group has been formed by reacting the steroid 3,20-dione withethylene, propylene, 1,2-, 1,3-, or 2,3-butylene glycol 01' pentane,hexane, heptane, or octane-diols wherein the alcohol groups are invicinal positions such as 1,2, 2,3, 3,4, or the like, or separated byone carbon atom such as 1,3, 2,4, 3,5, and the like, with an organicperacid such as performic, peracetic, perbenzoic, monoperphthalic acid,or the like. For the purpose of this invention, starting compoundshaving the ethylene ketal groups are preferred, since these ketals aregenerally more easily prepared in high yield than ketals produced by thereaction of the 3,20-diketo compounds with higher alkanediols.

PREPARATION 2 501,115,] 7u,21-tetrahydr0xy-6;i-methylallopregnane-3,20-dione 3,20-bis-(ethylene ketal) A solution of 1.115 grams of5u,6a-oxido-11fl,l7ot,2ltrihydroxyallopregnane-3,20-dione 3,20 bis(ethylene ketal) in 165 milliliters of tetrahydrofuran (thetetrahydrofuran being dried through distillation over lithium aluminumhydride) was added dropwise to a solution of milliliters of methylmagnesium bromide in ether (methyl magnesium bromide having a four molarconcentration). To this mixture was added 575 milliliters of benzene andthe reaction mixture was thereupon allowed to stir and reflux for 26hours. After cooling, the reaction mixture was poured into 700milliliters of iced, saturated ammonium chloride solution, stirred for aperiod of thirty minutes, and the benzene layer separated from theaqueous layer. The aqueous phase was extracted with three ZOO-milliliterportions of ethyl actate and the extracts added to the benzene layer.The combined benzene-ethyl acetate solution was thereupon washed withwater, dried over anhydrous sodium sulfate and evaporated to dryness togive 1.314 grams of crude solid. Trituration of this material with etherleft 1.064 grams of crystalline product of melting point 221 to 230degrees. Recrystallization of this material gave50:,1lfl,170:,2l-tfi118hYd1'0XY-6/3- methylallopregnane-3,20-dione3,20-bis-(ethylene ketal) of melting point 228 to 233 degrees androtation [al minus eleven degrees in chloroform.

Analysis.-Calcd. for C H O c, 64.70; H, 8.72. Found: C, 64.29; H, 8.69.

7 PREPARATION a 5u,1 I 9;] 7;x,21 -tetrahydroxy-68-12thylall0pregnane-3,20-dione 3,20-bis-(ethylene ketal) In thesamemanner as shown in Preparation 2, 50:,641- 5 oxido-l 1 3,17t,21-trihydroxyallopregnane-3,20-dione 3,20- bis-( ethylene ketal), wasreacted with ethyl magnesium ,bromide in ether solution to give thecorresponding 5a, 11p,l7a,21-tetrahydroxy-6fi-ethylallopregnane 3,20dione 3,20-bis-(ethylene ketal).

In the same manner as shown in Preparations 2 and 3, other 51x, 1 1,3,171:4,2l-tetrahydroxy-613-alkylallopregnane-3, 20-dione 3,20bis-(ethylene ketals) are prepared by reacting the corresponding50,6u-0Xid0-1lfi,l7oz,Z1t1ihydr0Xyallopregnane-3,20-dione3,20-bis-(ethylene ketal) with a metal alkyl or metal aryl morespecifically an alkyl metal halide such as a Grignard reagent, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,hexyl, and phenyl magnesium bromides and iodides or cadmium alkyl andcalcium alkyl and phenyl bromides or iodides. Representative6p-alkylated allopregnanes thus prepared include:50:,11B,17a,2l-tetrahydroxy-6t3 propylallopregname-3,20-dione3,20-bis-(ethylene ketal), 50,1IB,170L,21-tetrahydroxy-6B-butylallopregnane-3,20-dione 3,20 bis- (ethylene ketal),5a,11B,17,21-tetrahydroXy-6fi-isobutylallopregnane-3,20-dione3,20-bis-(ethylene ketal), 50;,11/3,

17u,21-tetrahydroxy-Gfi-pentylallopregnane-3,20-dione 3,

20-bis-(ethylene ketal),50:,11,8,17a,21-tetrahydroxy-6ehexylallopregnane-3 ,20-dione 3 ,20-bis-(ethylene ketal 5a,11B,17 x,21-tetrahydroxy-6,8-phenylallopregnane 3,20-dione 3,20-bis-(ethylene ketal), and the like.

PREPARATION 4 -5qt,I-1;B,I 7:1,21 -tetrahydrxy-6/3-methylall0pregnane-3,20- dione A solution was prepared containing 468milligrams of a,11fi,17u,21-tetrahydroxy-6B-methylallopregnane 3,20-dione 3,20-bis-(ethylene ketal), 38 milliliters of methanol and 7.7milliliters of 2 N sulfuric acid. This solution was refluxed for aperiod of thirty minutes, then neutralized with five percent dilutesodium bicarbonate solution (about 100 milliliters) and concentratedunder reduced pressure at 55 degrees centigrade to about 35 millilitersof volume. A product crystallized upon cooling and was recovered byfiltration. This product was recrystallized from acetone-Skellysolve Bhexanes to give an analytical-pure sample of5a,1lfi,17ot,21-tetrahydroxy- 6fl-methylallopregnane-3,20-dione ofmelting point 240 to 244 C. (decomposition) and rotation [(11 plus fortydegrees in dioxane.

Analysis.-Calcd. for C H O C, 66.98; H, 8.69. Found: C, 66.84; H, 8.86.

PREPARATION 5 511,115,] 70:,21 -tetrahydroxy-6 3-ethylall0pregnane-3,20-dione In the same manner as shown in Preparation 4, 5a,1l,8,17ec,2l-tetrahydroxy-6B-ethylallopregnane-3,20 dione 3,'20-bis-(ethylene ketal) was hydrolyzed with dilute sulfuric acid inethanol solution to give5a,llfi,17a,2l-tctrahydroxy-6fi-ethylallopregnane-3,ZO-dione.

In the same manner as shown in Preparations 4 and 5, hydrolysis of other5u,1118,l7zx,2l-tetrahydroxy-6,8-alkylal1opregnane-3,20-dione3,20-bis-(ethylene ketals), as well as those6fi-alkylallopregnane-3,20-dione 3,20-bis-(ketals) wherein the ketalgroup is other than ethylene, gives the corresponding5a,11,8,17ot,21-tetrahydroxy 6B alkylallo- .pregnane-3,20-diones such asfor example, 5ot,11{3,17ct,21- tetrahydroxy-6B-propylallopregnane-3,ZO-dione, 5u,1 1B, 170:,21-tetrahydroxy-63-butylallopregnane-3,20-dione, 50c,11B,l7e,2l-tetrahydroxy-6B-isobutylallopregnane 3,20- dione, 5a,l16,170;,21 tetrahydroxy-6B-pentylallopregnane- 3,20-dione,50,11/3,17,21-tetrahydroxy-6fi-hexylallopregnane-3,20-dione,5t,1-1p,17a,21 tetrahydroxy-6B-phenylallopregnane-3,20-dione and thelike.

8 PREPARATION 6 de methylhydrocortisone A stream of nitrogen was bubbledthrough a solution. of 429 milligrams of50,l1p,17a,21-tetrahydroxy-6,B-- methylallopregnane-3,20-dione containedin milliliters of denatured absolute alcohol for a period of tenminutes. "To this solution was added 4.3 milliliters of 0.1 normalsodium hydroxide solution which had likewise been treated with nitrogen.The mixture was allowed to stand in a nitrogen atmosphere for a periodof eighteen hours and thereupon was acidified with acetic acid, andconcentrated under reduced pressure at 55 degrees centigrade to dryness.The residue weighing 417 milligrams was recrystallized fromacetone-Skellysolve B hexanes to give in two crops 249 milligrams of6a-methylhydrocortisone melting between 184 and 194 degrees centigrade.An analytical sample was prepared melting at 203 to 208 degreescentigrade and consisting of 6a-methylhydrocortisone.

Analysis.Calcd. for C H O C, 70.18; H, 8.57. :FOUndI C, 70.32; H, 8.50.

The mother liquors contained besides 6m-methylhydrocortisone,substantial amounts of 6B-methylhydroco-rtisone which can be isolated byrecrystallization, papergram, countercurrentprocedures and other meansknown in the art.

Esterification of 6a-methylhydrocortisone with acetic anhydride inpyridine at room temperature yieded 6amethylhydrocortisone ZI-acetate ofmelting point 213 to 214 degrees centigrade.

Analysis.Calcd. for C I-1 ,0 C, 68.87; H, 8.19. Found: 'C, 68.60; H,8.41.

PREPARATION 7 6fi-methylhydrocortisone A solution was preparedcontaining 27.5 grams of 5a,ll,8,17a,21 tetrahydroxy 6Bmethylallopregnane- 3,20-dione in 6500 milliliters of ethanol denaturedwith .methanol. The solution was freed of air oxygen by bubblingoxygen-free nitrogen through it for a period of fifteen minutes. To thissolution was added a similarly air oxygen-free prepared solution ofone-tenth normal sodium hydroxide (235 milliliters). The solution wasallowed to stand at room temperature (about 22 to 24 degrees centigrade)in an inert nitrogen atmosphere for a period of twenty hours and wasthen acidified with fourteen milliliters of acetic acid. The thusobtained acid solution was evaporated at about fifty to sixty degreescentigrade in vacuo, the thus produced residue dissolved in 200milliliters of ethyl acetate and 200 milliltiers of water, the waterlayer separated from the organic layer and discarded, the organic layerwashed with 350 milliliters of five percent aqueous sodium bicarbonatesolution, then three times with water and thereupon dried over anhydroussodium sulfate and concentrated to a volume of 180 milliliters. Aftercooling the 180 milliliters of solution in a refrigerator (about fivedegrees centigrade), the solution was filtered giving 11.9 grams ofmaterial. This material was redissolved in 500 milliliters of ethylacetate, the ethyl acetate solution was concentrated to 150 milliliters,refrigerated as before to give 6.15 grams of crude6fl-methylhydrocortisone of melting point 220 to 223 degrees centigrade.

Recrystallization of the crude li-methylhydrocortisone three more timesfrom ethyl acetate gave an analytical sample of 6fl-methylhydrocortisonewith melting point 223 to 227 degrees centigrade, rotation [otl plusdegrees in acetone; ultraviolet absorption A pag 243 m a =14,-50O

' "Fotlndlc, 70.54; H, 8.91.

g PREPARATION 8 6m-ethylhydrocortisone In the same manner as shown inPreparation 6, 5a, 11B,l7a,21 tetrahydroxy 6oz ethylallopregnane 3,20-dione was treated with a solution of potassium hydroxide in methanol togive at room temperature 6a-ethylhydrocortisone of melting point 223 to226 degrees centigrade and In the same manner dehydrating with an alkalimetal hydroxide in alcoholic solution other 5a,11]3,17oc,21-tetrahydroxy 6B alkylallopregnane 3,20 diones produced the corresponding6a-alkyl-11fl,17a,21-trihydroxy- 6-alkyl-4-pregnene-3,20-diones such asoat-propylhydrocortisone, 6a-butylhydrocortisone,6a-isobutylhydrocortisone, 6a-penty1hydrocortisone,oa-hexylhydrocortisone, 6a-phenylhydrocortisone and the like.

PREPARATION 9 1-dehydr0-6a-methylhydrocortisone (6 a-methyl-I 1 3,] 7a,21 -trihydroxy-1 ,4-pregnadiene-3,20-dine) 'Six 100-milliliter portionsof a medium in 250-milliliter Erlenmeyer flasks containing one percentglucose, two percent corn steep liquor (sixty percent solids) and tapwater was adjusted to a pH of 4.9. This medium was sterilized for 45minutes at fifteen pounds per square inch pressure and inoculated with aone to two day growth of Septomyxa afiinis A.T.C.C. 6737. The Erlenmeyerflasks were shaken at room temperature at about 24 degrees centigradefor a period of three days. At the end of this period, this600-milliliter volume was used as an inoculum for ten liters of the sameglucosecornsteep liquor medium which in addition contained tenmilliliters of an antifoam (a mixture of lard oil and octadecanol). Thefermentor was placed into the water bath, adjusted to 28 degreescentigrade, and the contents stirred (300 rpm.) and aerated (0.5 l. ofair/ min./ 10 1. of beer). After seventeen hours of incubation, when agood growth developed and the acidity rose to pH 6.7, two grams of6a-methylhydrocortisone plus one gram of 3-ketobisnor-4-cholen-22-al,dissolved in 115 milliliters of dimethylformamide, was added and theincubation (conversion) carried out at the same temperature and aerationfor 24 hours (final pH 7.9). The mycelium (56 grams dry weight) wasremoved by filtration and the steroidal material was extracted from thebeer with methylene chloride, the methylene extracts evaporated todryness, and the resulting residue chromatographed over a Florisilsynthetic magnesium silicate column. The column was packed with 200grams of Florisil and was developed with five 400-milliliter fractionseach of methylene chloride, Skellysolve B-acetone mixtures of 9:1, 8:2,7:3, 1:1, and methanol. The fraction eluted with Skellysolve B-acetone(7:3) weighed 1.545 g. and on recrystallization from acetone gave, inthree crops, 928 milligrams of product of melting point 210 to 235degrees centigrade. The sample prepared for analysis melted at 245 to247 degrees centigrade. Rotation [al was plus 83 degrees in dioxane.

Analysis.Calcd. for C H O C, 70.56; H, 8.08. Found: C, 70.53; H, 7.94.

Instead of by fermentative dehydrogenation,l-dehydro-6a-methylhydrocortisone or an ester thereof can be obtained bydehydrogenation of 6a-methylhydrocortisone or an ester thereof withselenium dioxide as illustrated in Preparation .10. 7

1O PREPARATION 1o 1-dehydro-6a-methylhydrocortisone acetate A mixture ofseventy milligrams of fia-methylhydrocortisone acetate in 4.5milliliters of tertiary butyl alcohol and 0.45 milliliter of acetic acidand 24 milligrams of selenium dioxide was heated to 75 degreescentigrade. and stirred for 24 hours. Thereafter another 24-milligramportion of selenium dioxide was added and heated to 75 degreescentigrade and stirring continued. Thereafter the mixture was cooled,filtered to remove the selenium dioxide and evaporated. Paperchromatography showed the residue to contain about fifty to 55 percentof 1-dehydro-6a-methylhydrocortisone acetate which can be recovered fromthe residue by recrystallization and chromatography.

Infrared absorption in Nujol mineral oil suspension:

11- and 2l-ket0 conj'igated 3-keto A -double bond a, 400 a, 280 cmr 1,722 1, 700 1 PREPARATION 1 1 1-dehydr0-6,B-methylhydrocortisone In themanner shown in Preparation 11, by fermentation with microorganisms ofthe genera Corynebacterium, Didymella, Calonectria, Alternaria,Collectotrichum, Cylindrocarpon, Ophiobolus, Septomyxa, Fusarium,Listeria or Erysipelothrix:

(a) 6-ethylhydrocortisone (6ocor 6B-epimer) yielded the correspondingl-dehydro-6-ethylhydrocortisone.

(b) 6-propylhydrocortisone yielded 1-dehydro-6-pro pylhydrocortisone.

(c) -butylhydrocortisone yielded 1-dehydro-6-butylhydrocortisone.

(d) 6-hexylhydrocortisone yielded 1-dehydro-6-hexylhydrocortisone.

(e) 6-phenylhydrocortisone phenylhydrocortisone.

In the same manner as shown in Preparations 9 and 11, other1-dehydro-6-alkyland 1-dehydro-6-arylhydrocortisones are produced bysubjecting the corresponding 6-alkylated or 6-arylated hydrocortisone orthe esters thereof to fermentation especially by Corynebacterium simplexor Septomyxa afiinis in the absence or presence of steroidal promoterssuch as 3-ketobisnor-4-cholen-22- a1, crude11B,21-dihydroxy-1,4,17(20)-pregnatrien-3-one, 3-ketobisnor-4-cholenicacid and progesterone. Representative l-dehydro-oot-alkyland1-dehydro-6a-arylhydrocortisones thus produced include:1-dehydro-6avalerylhydrocortisone, 1-dehydro-6a-hexylhydrocortisone,1-dehydro-6oc-isobutylhydrocortisone,1-dehydro-6u-isopropylhydrocortisone, and the like.

PREPARATION 13 1-dehydr0-6o-methylhydrocortiso'ne acetate yielded1-dehydro-6- A mixture was prepared containing 500 milligrams of1-d6hYdIO-6oc-1116ihYlhYdIOCOItiSOI16 in five milliliters of pyridineand five milliliters of acetic anhydride. The mixture was maintained atroom temperature (22 to 24 degrees centigrade) for a period of sixhours, thereupon poured into milliliters of ice water and the resultingaqueous mixture extracted with three 25-milliliter portions of methylenechloride. The combined methylene chloride solutions were washed, driedover sodium sulfate and evaporated and the thus obtained residuerecrystallized three times from acetone-Skellysolve B PREPARATION 14 Inthe same manner as given in Example 13, treating in pyridine solution:

(a) 1-dehydro-6ot-methylhydrocortisone with propionic anhydride yielded1-dehydro-6a-methylhydrocortisone 2l-propionate.

(b) l-dehydro-6a-methylhydrocortisone with butyric anhydride yieldedl-dehydro-6ot-methylhydrocortisone 2lbutyrate.

(c) l-dehydro-6a-methylhydrocortisone with valeric anhydride yieldedl-dehydro-6a-methylhydrocortisone 2lvalerate.

(d) l-dehydro-6ot-methylhydrocorti'sone with hexanoyl bromide yielded1-dehydro-u-methylhydrocortisone 21- hexanoate.

(e) 1-dehydro-6ot-methylhydrocortisone with octanoyl chloride yielded1-dehydro-6u-methylhydrocortisone 21- octanoate.

(f) 1-dehydro-6a-rnethylhydrocortisone with benzoyl chloride yielded1-dehydro-6tx-methylhydrocortisone 2lbenzoate.

(g) 1-dehydro-6a-methylhydrocortisone with phenylacetyl chloride yielded1-dehydro-6tz-methylhydrocortisone 21-phenylacetate.

(h) 6a-ethylhydrocortisone with acetic anhydride yieldedl-dehydro-6a-ethylhydrocortisone acetate.

In a manner similar to Preparations 13 and 14, other starting materialscan be made by esterifying l-dehydro- 6-alkylhydrocortisone orl-dehydro-6-arylhydrocortisone in pyridine solution with acyl halides oracid anhydrides. In similar manner the esters of 6-alkylhydrocortisoneand 6-arylhydrocortisone can be prepared and may be used in the examplesof the instant invention. Starting materials thus prepared include theacetates, propionates, butyrates, isobutyrates, valerates, isovalerates,hexanoates, heptanoates, octanoates, benzoates, phenylacetates, B-cyclopentylpropionates, phenylpropionates, laureates, hemisuccinates,tartrates, maleates, toluenesulfonates, and the like of1-dehydro-6-alkylhydrocortisone and l-dehydro-6-arylhydrccortisonewherein the alkyl group is methyl, ethyl, propyl, butyl, pentyl or hexyland the aryl group may be phenyl or the like.

EXAMPLE 1 6oz methyl 170:,21 dihydrxy-1,4,9(I1) pregnatriene- 3,20-dione21 -acetate To a solution of 530 milligrams of fiat-methyl-llp,17a.2l-tr hydroxy-l.4-nregnadiene-3.ZO-dione Zl-acetate(1-dehydro-6a-methylhydrocortisone 21-acetate) in five milliliters ofpyridine, in an atmosphere of nitrogen, was added 225 milligrams ofN-bromoacetarnide. After standing at room temperature under nitrogen fora period of thirty minutes, the reaction solut on was cooled to ten tofifteen degrees Centigrade and, with shak ng, sulfur dioxide gas waspassed over the surface until the solution gave no color with acidifiedstarch-iodine paper. During the addition of sulfur d oxide gas, thereaction became warm. The temperature was kept under thirty degreescentigrade by external cooling and by varying the rate of sulfur dioxideaddition. After standing at room temperature for a period of fifteenminutes, the reaction mixture was poured into thirty m lliliters of icewater and the resulting gummy precipitate extracted with fiftymilliliters of ether. The ether extract was washed with five percenthydrochloric acid solution and water, dried over anhydrous sodiumsulfate, and evaporated to dryness to give 371 milligrams of material.This material was recrystallized from acetone-Skellysolve B hexanes togive 318 m lligrams of 6ot-methyl-l7tx,2ldil1ydroXy-l,4,9(11)-pregnatriene-3,20-dione 21-acetate of melting point 188 to 191.5degrees centigrade.

EXAMPLE 2 6a -methyl 9oz bromo 11,6,17ot,21 trihydroxy 1,4-pregnadiene-3,20 dione 21 acetate (1 dehydro6amethyl-9a-br0m0hydr0cortis0ne 21-acetate) To a solution of 332milligrams of 6e-rnethyl-17a,21- dihydroxy-1,4,9 11)-pregna-triene-3,20-dione 21-acetate in five milliliters of methylenechloride and 9.9 milliliters of tertiary butyl alcohol was added asolution of 0.83 milliliter of 72 percent perchloric acid in 5.8milliliters of water followed by a solution of 142 milligrams of N-bromoacetamide in 2.5 milliliters of tertiary butyl alcohol. Afterstirring the reaction mixture for fifteen minutes, a solution of 142milligrams of sodium sulfite in seven milliliters of water was added andthe reaction mixture was concentrated to a volume of about 25milliliters und'er reduced pressure at about sixty degrees centigrade.At this point crystallization started. The concentrate was cooled in anice bath while stirring and 35 milliliters of water was added. Afterstirring for a period of twenty minutes, the crystalline product wasisolated by filtration, the crystals were washed with water andair-dried to give 406 milligrams of 6a-methyl-9a-bromoll,8,l7u,21-trihydroxy 1,4 pregnadiene 3,20 dione 2l-acetatel-dehydro-6ot-methyl-9ot-bromohydrocortisone 21-acetate) of meltingpoint 173 to 177 degrees centigrade (with decomposition).

EXAMPLE 3 60: methyl 95,11 8 oxido 17u,21 dihydroxy 1,4-

pregnadiene-3,20-dione 21 -acetate To a solution of 406 milligrams of6tx-rnethyl-9otbromo 115,17ot,2l trihydroxy 1,4 pregnadiene 3,20- dioneZI-acetate in fifteen milliliters of acetone was added 406 milligrams ofpotassium acetate and the resulting suspension was heated under refluxfor a period of eighteen hours. The mixture was then concentrated tofive milliliters of volume on the steam bath and thereupon tenmilliliters of water was added. This caused the potassium acetate to gointo solution and the steroidal product to crystallize out. The productwas separated by filtration and recrystallized from acetone to give intwo crops 232 milligrams of 6a-methyl-9/il,llfi-oxido l7a,21-dihydroxy-1,4-pregnadiene-3 ,20-dione 21-acetate of melting point255 to 263 degrees Centigrade.

EXAMPLE 4 6oz methyl 91x fluoro 11,8,17ot-2] trihydroxy 1 4- pregnadiene3,20 dione 2] acetate (1 dehydroot-methyl-9ot-flzzorohydrocortisone 21-acetate) To a solution of 230 milligrams of 60-I11thy1-9fi,11 8-oxido-l7et,2l-dihydroxy-l,4 pregnadiene-3,20-dione 21- acetate in fivemilliliters of methylene chloride was added 1.2 milliliters of 48percent solution of hydrogen fluoride. The two-phase mixture was stirredfor a period of twenty hours, then diluted with fifteen milliliters ofmethylene chloride and carefully poured into forty milliliters of watercontaining four grams of sodium bicarbonate. After shaking to neutralizethe excess hydrogen fluoride, the methylene chloride was separated andthe water phase was extracted with more methylene chloride. The combinedmethylene chloride solution (about milliliters) was dried over anhydroussodium sulfate, diluted with 25 milliliters of ether and chromatographedover twenty grams of Florisii synthetic magnesium silicate. The columnwas eluted as follows:

TABY-E I Fraction No. Solvent 1 (1')) milliliters) 2-6 (4' milliliterseach) 7-16 (4') milli i ers each) 16-21 (4'1 mi i i ers each).. 21- 6(4') millili ers eac 27-30 (4') milliliters each) 13 Fractions 2 to 13,inclusive, containing a total of 140 milligrams, were combined,evaporated and the residue thus obtained recrystallized fromacetone-Skellysolve B hexane and from methylene chloride to give 89milligrams of 6u-methyl-9a-fluoro-1118,17u,21-trihydroxy-1,4-pregnadiene-3,20-dione ZI-acetate (1-dehydro-6a-methy1-9a-fiuorohydrocortisone 21-acetate) of melting point 233 to 237 degreescentigrade. The ultraviolet absorption is as follows:

A2385 m a =15,325.

The infrared absorption measured in Nujol mineral oil is as follows:hydroxyl, 3430 cm.- 21-acetoxy-20-keto, 1735, 1717 cm.- conjugated3-keto group, 1658 cmr A -double bonds, 1615, 1610 cm.- acetate CO bond,1270, 1239 cm.-

EXAMPLE 5 6 a-methyl-9auoro-I711,21-dihydrxy-1,4-pregnadiene-3,11,20-tri0ne 21 -acetate (1-dehydr0-6a-methyl-9auorocortisone 21-acetate) A solution was prepared containing in one milliliter of aceticacid fifty mlligrams of 6a-methyl-9a-fluoro-11B,170:,2l-trihydroxy-1,4-pregnadiene-3,20-dione 21-acetate, twentymilligrams of chromic anhydride and one drop (approximately fiftymilligrams) of water. This mixture was shaken several times at roomtemperature and allowed to stand for four hours. Thereafter it waspoured into ten milliliters of water and refrigerated for twenty hoursat about five degrees centigrade. The steroid which separated from theaqueous mixture was collected on filter paper and recrystallized twotimes from acetone to give6a-methyl-9a-fluoro-17a,21-dihydroxy-1,4-pregnadiene-3,1 1,20-trione21-acetate (1-dehydro-6a-methyl- 9u-fluorocortisone 21-acetate) EXAMPLE6 6 a-methyl-9a-fluoro-1 1 5,1 7 01,21 -trihydroxy-4-pregnene-3,20-dione 21 -acetate In the same manner as shown in Example 1,611-1116111- yl 1l,B,17 x,21 trihydroxy 4 pregnene 3,20 dione 21-acetatewas treated with N-chlorosuccinimide to give the correspondingintermediate hypochlorite, i.e., 6oz methyl 11/3,17zx,21 trihydroxy 1,4pregnadiene- 3,20-dione llfi-hypochlorite 21-acetate, which was thentreated with gaseous sulfur dioxide to give 6OL-l'l1BthYl-17a,21-dihydroxy-4,9(11)-pregnadiene-3 ,20-dione 21-acetate.

Treating the thus-obtained6a-methyl-17a,21-dihydroxy-4,9(11)-pregnadiene-3,20-dione 21-acetatewith N- chloroacetamide in the presence of aqueous perchlo-ric acid asshown in Example 2 yielded the 6a-methyl-9uchloro 11fi,17oc,21trihydroxy 4 pregnene 3,20- dione 21-acetate.

Treating the thus-obtained Goa-nlCthYl-9oc-Chl01'O-11B, 1701,21trihydroxy 4 pregnene 3,20 dione 21- acetate with potassium acetate inacetone solution under reflux conditions, as shown in detail in Example3, gave the corresponding 60c methyl 913,116 oxido 17,21-dihydroxy-4-pregnene-3,20-dione 21-acetate.

Treating the thus-obtained 6a-methyl-9 8,11B-oxido- 17a,21 dihydroxy 4pregnene 3,20 dione 21- acetate with hydrogen fluoride in chloroformsolution produced the 6m methyl 9a fluoro l1B,17a,21-trihydroxy-4-pregnene-3,ZO-dione 21-acetate.

EXAMPLE 7 6a methyl 9a fluoro 1701,21 dihydroxy 4 pregnene-3,I I,20-trione 21-acetate Oxidizing in the manner shown in Example 6amethyl9a fluoro 11B,l7oc,21 trihydroxy 4 pregnene-3,20-dione 2l-acetate withchromic anhydride produces the 60: methyl 9a fluoro 17OL,21 dihydroxy4-pregnene-3 ,l 1,20-trione 21-acetate (6a-methyl-9a-fiuorocortisone21acetate) In the same manner as given in Examples 1 through 7 but usingas starting material the corresponding 65- isomers in the sequenceillustrated in particular by Examples 1 through 5, are obtained6,8-methyl-9a-fluoro- 11;3,l7a,21 trihydroxy 1,4 pregnadiene 3,20 dione21 acetate, 6,9 methyl 9a fluoro 1711,21 dihydroxy 1,4 pregnadiene3,11,20 trione 21 acetate, 6 3 methyl 9a fluoro 11;3,17a,21 trihydroxy4- pregnene 3,20 dione 21 acetate, 6,8 methyl 9ozfluoro 17a,21 dihydroxy4 pregnene 3,11,20- trione 21-acetate. Using instead of the acetates,other esters as starting materials in the series exemplified by Examples1 through 5, such as propionate, butyrate, isobutyrate, valet-ate,benzoate, hexanoate, heptanoate, octanoate, phenylacetate,phenylpropionate, laurate, or the like of 6aor 6B-methylhydrocortisoneor 1-dehydro-6uor 6B-methylhydrocortisone yields the correspondingesters of 6aor 6B-methyl-9a-fluorohydrocortisone or of 1-dehydro-6a-methyl 9u-fluorohydrocortisone and -cortisone. Instead of the6a-methylhydrocortisone and l-dehydro-6a-methylhydrocortisone, other1-dehydro-6-alkyland l-dehydro-6-arylhydrocortisones can be used to giveby the sequence of steps illustrated in Examples 1 through 5 thecorresponding 6m-alkyl-9a-fluorohydrooortisone ters, or respectively the1-dehydro-6waryl-9a-fluorohydrocortisone esters and the ll-ketoanalogues, i.e., l-dehydro-6a-alkyl-9a-fluorocortisone esters andl-dehydro- 6a-aryl-9a-fluorocortisone esters, wherein the alkyl groupscan be ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and thearyl group can be phenyl, benzyl or the like.

EXAMPLE 8 6a methyl c fluoro 11/3,17u,21 trihydroxy 1,4- pregnadiene3,20 dione (I dehydro 6a methyl- 9a-fluorohydr0cortis0ne) milligrams of6a-methyl-9a-fluoro-l1B,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione21-acetate were dis solved in a solution consisting of two millilitersof methanol and 0.1 milliliter of water, previously purged of airoxygenby passing nitrogen through it, and thereto was added fifty milligramsof potassium carbonate. The mixture was allowed to stand at roomtemperature for a period of six hours in a nitrogen atmosphere,thereupon neutralized with five percent aqueous hydrochloric acidsolution, diluted with five milliliters of water and refrigerated. Themixture was then filtered and the soids recrystallized fromacetone-Skellysolve B hexanes to give pure 6a-methyl-9a-fluoro-11/3,17x,21-trihydroxy- 1,4 pregnadiene 3,20 dione (1 dehydro6ozmethyl-9a-fluorohydrocortisone) EXAMPLE 9 6a methyl 9oz fluoro ;,21dihydroxy 1,4- pregnadiene 3,11,20 trione (I dehydro 60:methyl-9a-flu0roc0rtis0ne) In the manner given in Example 8, hydrolyzing6amethyl 9a fluoro 1701,21 dihydroxy 1,4 pregnadiene 3,11,20 trione 21acetate with potassium hydroxide in methanol yielded the6a-methyl-9u-fluoro- 17a,2l-dihydroxy-1,4-pregnadiene-3,11,20-trione(l-dehydro-6a-rnethyl-9a-fluorocortisone) EXAMPLE 1O In the same mannergiven in Example 8, hydrolyzing 6oz methyl 9m fiuoro l1,8,17oc,2ltrihydroxy 4- pregnene-3,20-dione 21-acet-ate with sodium hydroxide in anitrogen atmosphere produces 6ot-methyl-9ot-fluoro-11p,17a,21-trihydroxy-4-pregnene-3,20-dione(6a-methyl9afluorohydrocortisone).

In the manner given in Example 8, hydro'lyzing with sodium carbonate inethanol solution in a nitrogen atmosphere6ot-methyl-9a-fluoro-170:,2l-dihydroxy-4-pregnene- 3,11,20-trione21-acetate yielded 6a-methyl-9a-fluoro-17a,21-dihydroxy-4-pregnene-3,20-dione (6ct-methyl-9afluorocortisone)EXAMPLE 12 6a methyl 9oz fluoro 1];3,17a,21 trihydroxy 1,4-pregnadiene-3,20-diorze ZJ-propionate(I-dehydro-Gozmethyl-9m-fluorohydrocortisone 21-propi0nate) A solutionwas prepared containing fifty milligrams of 60: methyl 9a fiuoro11,5,l70,21 trihydroxy 1,4- pregnadiene-3,20-dione in one milliliter ofpyridine and one milliliter of prop-ionic anhydride. The solution wasallowed to stand at room temperature for a period of 21 hours and wasthereupon poured into ten milliliters of water. The reaction mixture wasthen extracted with three lO-milliliter portions of methylene chloride,the methylene chloride extracts were combined, washed with Water, driedover anhydrous sodium sulfate and evaporated to give a residue which wasrecrystallized from ethyl acetate to give pure6a-methyl-9u-fiuoro-l113,17a,21- trihydroxy-1,4-pregnadiene-3,20-dione2l-propionate.

EXAMPLE 13 6a methyl 90c fluoro 11B,17a,21 trihydroxy 1,4-pregnadiene-3,20-dine ZI-benzoate (I dehydro6amethyl-9a-fluorohydrocortisone 21 -benz0ate) A solution was preparedcontaining 6u-methyl-9w fiuoro 11B,17a,21 trihydroxy 1,4 pregnadiene3,20- dione in one milliliter of benzoyl chloride and two milliliters ofpyridine. The mixture was allowed to stand overnight for a period ofeighteen hours and was thereupon diluted with ten milliliters of water.The water solution was extracted three times with methylene chloride,the methylene chloride fractions combined, washed with water, dried overanhydrous sodium sulfate and evaporated to give a residue. This residuewas recrystallized from methanol to give6ot-methyl-9a-fluoro-11,8,17u,21trihydroxy-l,4-pregnadiene-3,ZO-dione21-benzoate.

EXAMPLE 14 6o: methyl 9m fluoro- 11B,17a,21 trihydroxy 1,4-pregxadiene-iZO-dione 21 -hemz'succz'nate(I-dehydrofiat-m6th)[-9a-flUOIOhydI'OCOITiSOIZE 21 -hemisuccinate) Asolution was prepared containing 0.5 gram of succinic anhydride, 0.1gram of 6a-methyl-9ot-fluoro-l lfi,l7rx,2l-trihydroxy-1,4-pregnadiene-3,20-dione in five milliliters ofpyridine. The solution was allowed to stand overnight for a period oftwenty hours, was thereupon diluted with water and the mixturerefrigerated and filtered. The precipitate thus collected on filterpaper was recrystallized two times from methanol to give 6ix-rnethyl-9a. fiuoro 1lB,17ix,21 trihydroxy 1,4 pregnadiene- 3 ,20-clioneZI-hemisuccinate.

EXAMPLE 15 6a methyl 9a fluoro 11,8,17a,21 trihydroxy 1,4-

pregnadz'ene-jjmdione 21-hemisuccinale sodium salt (1 -clehydr0-6a-metltyl-9afluorohydrocortisone 21 -hemisuccz'naze sodium salt) Sodiumhydroxide solution (0.1 normal) was slowly added to a stirred solutionof 100 milligrams of 6m-methyl 9c: fluoro llfi,l7m,2l trihydroxy 1,4pregnadione-3,20-dione 2lhemisuccinate, dissolved in two milliliters ofacetone, until the pH rose to about 7.4. During the addition of sodiumhydroxide solution, five milliliters of water was also added. Thesolution was then concentrated at 25 degrees centigrade under vacuum toremove the acetone. The resulting aqueous solution of 60a methyl 9afluoro 1l;3,17a,21 trihydroxy 1,4- pregnadiene-3,20-dioneZI-hemisuccinate sodium salt was filtered, freeze-dried andrecrystallized to give pure 6amethyl 9a fluoro 11,8,l7u,21 trihydroxy1,4 pregnadiene-3,20-dione ZI-hemisuccinate sodium salt.

EXAMPLE 16 In the same manner given in Examples 12 through 14, reactingin pyridine solution at room temperature (twenty to thirty degreescentigrade) (a) 1-dehydro-6a-methyl-9'a-fiuorohydroc0rtisone withbutyric anhydride yielded 1-dehydro-6ot-methyl-9a-fluorohydrocortisone21-butyrate.

(b) 1-dehydro-6a-methyl-9ix-fluorohydrocortisone with valeric anhydrideyielded 1-dehydro-6a-methyl-9ix-fluorohydrocortisone 2l-valerate.

(c) l-dehydro-6armethyl-9oc-fiuorohydrocortisone with lauryl chlorideyielded l-dehydro-6a-methyl-9u-fluorohydroco-rtisone 21-laurate.

(d) l-dehydro6a-methyl-9ix-fluorohydrocortisone with phenylacetylchloride yielded l-dehydro-6oc-methyl-9ufluorohydrocortisoneZI-phenylacetate.

(e) 1-dehydro-6a-methyI-Qwfluorohydrocortisone with phenylpropionylbromide yielded 1-dehydro-6a-methyl- 9et-fluorohydrocortisone2l-phenylpropionate.

(f) l-dehydro-6ot-methyl-9a-fluorohydrocortisone withfl-cyclopentylpropionyl chloride yieldedl-dehydro-Gamethyl-9u-fiuorohydrocortisone 21-(fi-cyclopentylpropionate).

(g) 1-dehydro-6wmethyl-9a-fiuorocortisone with propionic anhydrideyielded 1-dehydro-6u-methyl-9u-fluorocortisone 2l-propionate.

(h) 1-dehydro-6ot-methyl-9a-fluorocortisone with valeric anhydrideyielded l-dehydro-6u-methyl-9ot-fluorocortisone 21-valerate.

(i) l-d-ehydro-6a-methyl-Qwfluomcortisone with benzoyl chloride yielded1-dehydro-6a-methyl-9u-fiuorocortisone 2l-benzoate.

(j) l-dehydro-6a-methyl-9a-fluorocortisone with phenylacetyl chlorideyielded 1-dehydro-6ot-methyl-9otfiuorocortisone 21-phenylacetate.

(k) 1-dehydro-6m-methyl-9a-fluoroco-rtisone with undecylenyl chlorideyielded 1-dehydro-6ot-methyl-9a-fluorocortisone ZI-undecylenate.

(l) 6ix-methyl-9a-fluorohydrocortisone with propionyl anhydride yielded6a-methyl-9u-fiuorohydrocortisone 21- propionate.

(m) 6ut-methyl-9ix-fluorocortisone with propionyl' anhydride yielded6a-methyl-9u-fiuorocortisone 2l-propionate.

EXAMPLE 1! 1-dehydr0-6a-methyl-9ot-flu0r0hydrocortisone 21-methanerulf0nate A solution was prepared containing 250 milligrams ofl-dehydro-6ix-methyl-9u-fluorohvdrocortisone in six milliliters ofpyridine. This solution was cooled to zero degrees centigrade andtreated with 0.25 milliliter of methanesulfonyl chloride. Thereafter thesolution was allowed to stir at a temperature between'zero and five derees centigrade for a period of eighteen hours. Thereafter ice and twomilliliters of w ter were added, followed by thirty milliliters ofsuificient dilute (five percent) hydrochlo ic ac d to neutralize tepyridine. The rnixture was then filtered. the precip tate washed withwater, and dried to give 197 milligrams of crude 6a methyl 9oz fluoro15.1%,21 trihydroxy 1,4- pregn-diene-320 dione ZI-rnethanesulfonate ofmelting point to degrees centigrade.

ow shing this m terialseveral times with water gave 1 dehydro 60c methyl90 fiuorohydrocortisone 2l- 17 fnethanesulfonate of melting point200-210 degrees centigrade, rotation [al -92 (in pyridine) and ale.

max.

1-dehydro-6a-methyl-9a-fluorohydrocortisone 21-methanesulfonate is aninteresting ester inasmuch as it has a high anti-inflammatory activity,measured in the granulorna pouch test and has no noticeableglucocorticoid activity. This split of activity makes this compoundparticularly valuable in the treatment of those arthritic patients wherechanges in the glycogen metabolism is undesirable.

The organic sulfonyl esters such as the 21-mesylate or the 21-t0sylateare additionally useful as intermediates for the preparation of6a-methyl-9a-fiuoro-115,17a-dihydroxy-l,4-pregnadiene-3.20-dione asshown in U.S. Patent No. 2,867,637.

Oxidation of 1-dehydro-6a-methyl-9a-fiuorohydrocortisone21-methanesulfonate in acetic acid solution with chromic anhydride at atemperature between minus ten and fifty degrees centigrade, preferablyat room temperature, give the l-dehydro-6a-methyl-9a-fiuorocortisoneZI-methanesulfonate which has anti-inflammatory activity.

In a manner similar to Examples 12 through 14 and 16, other esters of1-dehydro-6a-methyl-9a-fluorohydro cortisone and1-dehydro-6a-methyl-9a-fiuorocortisone as well as esters of6a-methyl-9a-fluorohydrocortisone and 6a-methyl-9a-fluorocortisone areprepared by reacting these steroids with the anhydride or acyl halidesof organic carboxylic acids, particularly hydrocarbon carboxylic acidscontaining from one to twelve carbon atoms, inclusive. Representative21-esters thus prepared include in particular, besides those of thebefore-mentioned examples, the butyrates, isobutyrates, valerates,isovalerates, hexanoates, heptanoates, octanoates, benzoates,phenylacetates, phenylpropionates, B-cyclopentylpropionates, tertiarybutylacetates, toluates, Z-furoates, benzenesulfonates,toluenesulfonates, and the like of 1-dehydro-6u-methyl-9a-fluorohydroeortisone, l-dehydro-6a-methyl-9a-fluorocortisone, 6u-methyl-9a-fluorohydrocortisone and6m-methyl-9a-fiuorocortisone. In the same manner 21-esters of the6fi-methyl epimers and the 21- esters of the 6ozand 6,8-alkyland arylanalogues of these compounds can be prepared.

Treating the 1-dehydro-6-methyl-9a-halohydrocortisones and -cortis0nes,wherein the halogen atom is chlorine, bromine or iodine, with anacylating agent selected from halides or anhydrides of organiccarboxylic acids, especially hydrocarbon carboxylic acids containingfrom 238-1-239 millimicrons, E= 15,000

18 one to twelve carbon atoms, inclusive, preferably at room temperaturein pyridine solution produces the cor-re sponding 21-esters of1-dehydro-6-methyl-9a-halohydrocortisone and1-dehydro-6-methyl-9a-halocortisone.

The starting 1dehydro6-methyl-9a-halohydrocortisones and -cortis0neswherein the halogen is chlorine, bromine or iodine are produced byprocedures known in the art, such as reacting the6-methyl-17a,21-dihydroxy-1,4,9 (11)-pregnatriene-3,20-dione 21-ester(of Example 1) with N-bromo-, N-chloroor N-iodosuccinimide in thepresence of an acid as shown in Example 2 to give the corresponding6a-methyl-9a-halo-l 1/3, l7oa,21-trihydroxy- 1,4-pregnadiene-3,20-dione21-ester. Mild acid hydrolysis with dilute sulfuric acid at roomtemperature produces the corresponding free triol,1-dehydro-6u-methyl-9ahalohydrocortisone.

Oxidation of the6-methyl-9a-halo-l1B,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione21-ester with chromic anhydride yields the1-dehydro-6-methyl-9a-halocortisone 21-ester which by acid hydrolysis asmentioned above gives the free diol,1-dehydro-6-methyl-9u-halocortisone.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art, and the invention is therefore to be limited only by the scopeof the appended claims.

I claim:

1. A steroid selected from the group consisting of 1-dehydro-6-methyl-9a-fiuorohydrocortisone, l-dehydro-6-methyl-9a-fiuorocortisone, 1-dehydro-6-methyl-9a-fiuorohydrocortisone21-acylate and 1-dehydro-6-methyl-9afluorocortisone 21-acylate whereinthe acyl group is selected from the group consisting of acyl radicals ofhydrocarbon carboxylic acids containing from one to twelve carbon atoms,inclusive, and methanesulfonic acid.

2. 1-dehydro-6a-methyl-9a-fiuorohydrocortisone.

3. 1 dehydro c methyl 9oz fiuorohydrocortisone 21-acetate.

4. 1 dehydro 6a methyl 9a fluorohydrocortisone ZI-methanesulfonate.

5. 1-dehydro-6a-methyl-9a-fiuorocortisone.

6. 1-dehydro-6a-methyl-9a-fluorocortisone 21-acetate.

References Cited in the file of this patent UNITED STATES PATENTS

1. A STEROID SELECTED FROM THE GROUP CONSISTING OF 1DEHYDRO-6-METHYL-9A-FLUOROHYDROCORTISONE, 1-DEHYDRO-6METHYL-9A-FLUOROCORTIRISONE, 1-DEHYDRO-6-METHYL-9A-FLUOROHYDROCORTISONE 21-ACYLATE AND 1-DEHYDRO-6-METHYL-9AFLUOROCORTISONE 21-ACYLATE WHEREIN THE ACYL GROUP IS SELECTED FROM THE GROUP CONSISTING OF ACYL RADICALS OF HYDROCARBON CARBOXYLIC ACIDS CONTAINING FROM ONE TO TWELVE CARBON ATOMS, INCLUSIVE, AND METHANESULFONIC ACID. 